Pharmaceutical compositions of bisphosphonic acids, and salts thereof, are prepared by wet granulation tablet formulation. These pharmaceutical compositions are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget's disease, malignant hypercalcemia, and metastatic bone disease. These compositions are prepared without the addition of binder; instead, the drug itself acts as a binder.

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Claims(15)

We claim:

1. A process for the preparation of a tablet containing an active ingredient, which is the sole binder, selected from the group consisting of:

12. The process of claim 11 wherein the lubricant is magnesium stearate.

13. The process of claim 4 which comprises the steps:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, and lactose with a high shear granulator for 3 to 5 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with the high shear granulator,

(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12 to 24 hours in a tray dryer,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium disintegrant with a ribbon blender or a planetary mixer for 3 to 8 minutes,

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

14. The process of claim 4 which comprises the steps:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, and lactose with a planetary granulator for 10 to 25 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 10 minute period to form granules with the planetary granulator,

(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium disintegrant with a ribbon blender or a planetary granulator for 3 to 8 minutes, and

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

15. The process of claim 4 which comprises the steps:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, and lactose with a high shear granulator for 3 to 5 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with a high shear granulator,

(3) drying the granules to remove water by the use of heated air for 10 minutes to one hour using a fluid bed dryer,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium disintegrant with a ribbon blender for 3 to 8 minutes,

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

Description

RELATED APPLICATIONS

This application is a continuation of Ser. No. 10/090,541, filed Mar. 4, 2002 now abandoned, which is a continuation of U.S. application Ser. No. 09/783,833 now abandoned, filed Feb. 15, 2001, which is a continuation of a twice filed continuing prosecution U.S. application Ser. No. 09/099,828 now abandoned, filed Jun. 18, 1998, which in turn is a continuation of U.S. application Ser. No. 09/236,904, filed Apr. 29, 1994, now abandoned.

BACKGROUND OF THE INVENTION

The pharmaceutical industry employs various methods for compounding pharmaceutical agents in tablet formulations. In particular, wet granulation is one of the most prevalent methods. Tablets prepared by wet granulation generally require the addition of a binding agent to keep the tablet together.

A variety of bisphosphonic acids have been disclosed as being useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following:

Wet granulated formulations need to have an agent called a “binder,” which, in contact with water, swells or starts dissolving, forming a gel-like consistency. Traditionally, starch, starch paste, gelatin, and cellulosics such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone are used as binding agents in wet granulation formulations. (See, Remington's Pharmaceutical Sciences, 18th ed, (Mack Publishing Company: Easton, Pa., 1990), pp. 1635-36). Microcrystalline cellulose, such as Avicel PH101, may be employed as a binder or compression aid in compositions prepared by dry granulation formulation, but microcrystalline cellulose functions primarily as a bulking agent in wet granulation formulations because the microcrystalline cellulose loses much of its binding properties upon wetting.

The wet granulation process helps to form agglomerates of powders. These agglomerates are called “granules.” The present invention provides for a wet granulated formulation of bisphosphonic acids and process therefor wherein the tablet formulation does not contain any binder. Instead, the drug itself acts as a binder. The absence of a separate binder keeps the formulation simpler, and minimizes adverse effects that binding agents can have on dissolution. Elimination of binder also simplifies the optimization and characterization of the formulation.

DESCRIPTION OF THE INVENTION

The present invention is directed in a first embodiment to a process for the preparation of pharmaceutical compositions of bisphosphonic acids by wet granulation formulation. This process employs a blend of a bisphosphonic acid and minimal amounts of other processing aids with no binder added. This tablet formulation is prepared by:

One particularly preferred process employs a high shear granulator as a mixer and comprises the steps of:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, such as Avicel PH101, and lactose with a high shear granulator for 3 to 5 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with the high shear granulator,

(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer, preferably with a fluid bed,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary mixer for 3 to 8 minutes, and

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

Another particularly preferred process employs a planetary granulator as a mixer and comprises the steps of:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose such as Avicel PH101, and lactose with a planetary granulator for 10 to 25 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 10 minute period to form granules with the planetary granulator,

(3) drying the granules to remove water by the use of heated air by drying 10 minutes to 1 hour with a fluid bed, or 12-24 hours in a tray dryer, preferably with a fluid bed,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender or a planetary granulator for 3 to 8 minutes, and

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

Still another particularly preferred process employs a high shear granulator as mixer, and comprises the steps of:

(1) forming a powder blend of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, microcrystalline cellulose, such as Avicel PH101, and lactose with a high shear granulator for 3 to 5 minutes,

(2) wet granulating the powder blend by the addition of water while mixing over a 3 to 5 minute period to form granules with a high shear granulator,

(3) drying the granules to remove water by the use of heated air for 10 minutes to one hour using a fluid bed dryer,

(4) milling the dried granules to a uniform size using a hammer type mill,

(5) adding and blending the disintegrant croscarmellose sodium NF type A with the dried milled particles for 3 to 8 minutes,

(6) adding and blending magnesium stearate lubricant to the mixture containing the croscarmellose sodium NF type A disintegrant with a ribbon blender for 3 to 8 minutes,

(7) compressing the lubricated granule mixture into a desired tablet form, and

(8) dedusting and storing the tablets.

Granulation is the process of adding water to a powder mixture with mixing until granules are formed. The granulation step may be varied from 2 to 30 minutes, preferably 2 to 5 minutes. The lubrication step is the process of adding lubricant to the mixture; the lubrication step may be varied from 30 seconds to 20 minutes, preferably 3 to 8 minutes.

The disclosed process may be used to prepare solid dosage forms, particularly tablets, for medicinal administration.

The disintegrant may be one of several modified starches or modified cellulose polymers, in particular, croscarmellose sodium is preferred. Croscarmellose sodium NF Type A is commercially available under the trade name “Ac-di-sol”.

Methods for the preparation of bisphosphonic acids may be found in, e.g., U.S. Pat. No. 3,962,432; U.S. Pat. No. 4,054,598; U.S. Pat. No. 4,267,108; U.S. Pat. No. 4,327,039; U.S. Pat. No. 4,407,761; U.S. Pat. No. 4,621,077; U.S. Pat. No. 4,624,947; U.S. Pat. No. 4,746,654; U.S. Pat. No. 4,922,077; and EPO Patent Pub. No. 0,252,504. In particular, methods for the preparation of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate may be found in U.S. Pat. No. 4,407,761 and U.S. Pat. No. 4,922,077, respectively.

The pharmaceutically acceptable salts of bisphosphonic acids may also be employed in the instant invention. Examples of base salts of bisphosphonic acids include ammonium salts, alkali metal salts such as potassium and sodium (including mono-, di- and tri-sodium) salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. The non-toxic, physiologically acceptable salts are preferred. The salts may be prepared by methods known in the art, such as in U.S. Pat. No. 4,922,077.

In the present invention it is preferred that the bisphosphonic acid is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid. It is even more preferred that the bisphosphonic acid is a sodium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, in particular, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.

Preferred pharmaceutical compositions comprise about 0.5 to 40% by weight of a bisphosphonic acid as an active ingredient; about 10 to 80% by weight of anhydrous lactose or hydrous fast flow lactose; about 5 to 50% by weight of microcrystalline cellulose; and about 0.1 to 5% by weight of magnesium stearate.

The preferred pharmaceutical compositions are generally in the form of tablets. The tablets may be, for example, from 50 mg to 1.0 g in net weight, more preferably 100 to 500 mg net weight, and even more preferably 150 to 300 mg net weight.

More preferred pharmaceutical compositions in accordance with the present invention comprise: about 0.5 to 25% by weight of a bisphosphonic acid selected from 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid and 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 30 to 70% by weight of anhydrous lactose or hydrous fast flow lactose; about 30 to 50% by weight of microcrystalline cellulose; about 0.1 to 2% by weight of magnesium stearate; and about 0.5 to 2% by weight of a disintegrant such as croscarmellose sodium.

Especially preferred pharmaceutical compositions comprise about 1 to 25% of the active ingredient, about 40 to 60% by weight of anhydrous lactose; about 35 to 45% by weight of microcrystalline cellulose; about 0.5 to 2% by weight of croscarmellose sodium; and about 0.1 to 1% by weight of magnesium stearate. Preferred pharmaceutical compositions as envisioned for commercial development are as follows.

Tablets of 2.5 mg potency free acid:

about 1.63% by weight of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 56.87% by weight of anhydrous lactose; about 40% by weight of microcrystalline cellulose; about 1% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate.

Tablets of 5 mg potency free acid:

about 3.25% by weight of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 55.25% by weight of anhydrous lactose; about 40% by weight of microcrystalline cellulose; about 1% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate.

Tablets of 10 mg potency free acid:

about 6.5% by weight of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 52.0% by weight of anhydrous lactose; about 40% by weight of microcrystalline cellulose; about 1% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate.

Tablets of 20 mg potency free acid:

about 13.0% by weight of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 45.5% by weight of anhydrous lactose; about 40% by weight of microcrystalline cellulose; about 1% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate.

Tablets of 40 mg potency free acid:

about 26.0% by weight of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonic acid monosodium salt trihydrate; about 32.5% by weight of anhydrous lactose; about 40% by weight of microcrystalline cellulose; about 1% by weight of croscarmellose sodium; and about 0.5% by weight of magnesium stearate.

Each of the tablets of the potencies above is preferably formulated in a 200 mg tablet containing 0.05 mL purified water USP per tablet.

The pharmaceutical tablet compositions of the present invention may also contain one or more additional formulation ingredients may be selected from a wide variety of excipients known in the pharmaceutical formulation art. According to the desired properties of the tablet, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparing tablet compositions. Such ingredients include, but are not limited to, diluents, compression aids, disintegrants, lubricants, flavors, flavor enhancers, sweetener and preservatives. The pharmaceutical tablet compositions of the present invention do not, however, require the addition of a separate binding excipient because in wet granulation the active ingredient itself acts as a binding agent.

The term “tablet” as used herein is intended to encompass compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or uncoated. Substances which may be used for coating include hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, talc, sweeteners, and colorants.

The pharmaceutical compositions of the present invention are useful in the therapeutic or prophylactic treatment of disorders in calcium or phosphate metabolism and associated diseases. These diseases can be divided into two categories:

2. Conditions which can benefit from a reduction in bone resorption. A reduction in bone resorption should improve the balance between resorption and formation, reduce bone loss or result in bone augmentation. A reduction in bone resorption can alleviate the pain associated with osteolytic lesions and reduce the incidence and/or growth of those lesions.

Increased bone resorption can be accompanied by pathologically high calcium and phosphate concentrations in the plasma, which would be alleviated by use of the instant pharmaceutical compositions.

The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.

EXAMPLE 1

Procedure for Manufacturing 2.5 mg Potency Tablets of

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

Per 10,000

Ingredients

Per Tablet

Tablets

Active ingredient

3.26 mg

32.6 g

(monosodium salt trihydrate)

Anhydrous Lactose, NF

113.74 mg

1137.4 g

Microcrystalline

80.0 mg

800.0 g

Cellulose NF

Magnesium Stearate

1.00 mg

10.0 g

Impalpable Powder NF

Croscarmellose Sodium

2.00 mg

20.0 g

NF Type A

The active ingredient (equivalent to 2.5 mg anhydrous free acid per tablet) was mixed with the microcrystalline cellulose NF and the anhydrous lactose NF in a high shear mixer for 3 minutes. Granulating solvent (550 mL water) was added to this blend with the mixer running over a two minute period. The wetted mass was dried in a fluid bed dryer at an inlet temperature of 50° C. The dried material was then milled using a FITZPATRICK J mill (hammer-type mill) to achieve fine granules. After milling, Croscarmellose Sodium NF type A (disintegrant) was added to the blend and mixed in a ribbon blender for 5 minutes. Magnesium Stearate Impalpable Powder NF (lubricant) was added to this blend through a #60 mesh screen and blended for an additional 4 minutes. The lubricated mixture was compressed to provide tablets of 2.5 mg active ingredient.

EXAMPLE 2

Procedure for Manufacturing 10 mg Potency Tablets of

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

Per 10,000

Ingredients

Per Tablet

Tablets

Active ingredient

13.05 mg

130.5 g

(monosodium salt trihydrate)

Anhydrous Lactose, NF

103.95 mg

1039.5 g

Microcrystalline

80.0 mg

800.0 g

Cellulose NF

Magnesium Stearate

1.00 mg

10.0 g

Impalpable Powder NF

Croscarmellose Sodium

2.00 mg

20.0 g

NF Type A

Tablets were prepared using essentially the procedure of Example 1.

EXAMPLE 3

Procedure for Manufacturing 20 mg Potency Tablets of

4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid

Per 10,000

Ingredients

Per Tablet

Tablets

Active ingredient

26.11 mg

261.1 g

(monosodium salt trihydrate)

Anhydrous Lactose, NF

90.89 mg

908.9 g

Microcrystalline

80.0 mg

800.0 g

Cellulose NF

Magnesium Stearate

1.0 mg

10.0 g

Impalpable Powder NF

Croscarmellose Sodium

2.0 mg

20.0 g

NF Type A

Tablets were prepared using essentially the procedure of Example 1.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the casual variations, adaptations, modifications, deletions, or additions of procedures and protocols described herein, as come within the scope of the following claims and its equivalents.

The Committee of Revision, The National Formulary, The United States Pharmacopeia, United States Pharmacopeial Convention (Bd of Trustees), Rockville, MD, Jan. 1, 1995; only title page and text p. 2238 supplied.